In the 1970s, Dr. Donald Wieland and his colleagues in the University of Michigan Medical School developed radioactive labeled meta-iodobenzylguanidine (MIBG) as a diagnostic contrast medium for adrenal medulla. The structure of the MIBG is similar to that of norepinephrine. It has been proved that tissues with normal sympathetic nerve distribution, such as hearts, salivary glands, and tumors that express neurohormone transporters, have high absorptivity for MIBG.
The first 131I-MIBG clinical report was published by the University of Michigan in 1980. The result shows that 123I-MIBG can be used for quantifying an expression level of amine in myocardial catecholamine. Since 1984, further studies have shown that high-dose 131I-MIBG can be further used for treating neuroblastoma. In 2012, the University of Michigan published The Report about the Therapy of 131I-MIBG, and the European Association of Nuclear Medicine (EANM) also published The Clinical Diagnosis Guideline for Pheochromocytoma in August, 2012, which is for the reference of clinical applications. At present, the radioactive iodine labeled MIBG has been widely applied to imaging diagnosis and treatment of neuroblastoma.
In recent years, the application of 123I-MIBG to the diagnosis of cardiac sympathetic functions gains more and more attention. 123I-MIBG myocardial scintigraphy has been proved valuable in diagnosing cardiomyopathy and heart failure, and especially in (1) predicting potential arrhythmia; (2) evaluating high-risk populations for heart failure; (3) improving knowledge about a reaction mechanism of elevated sympathetic activity in a heart failure. The 123I-MIBG can also be used for evaluating cardiac sympathetic functions of patients, so as to help choose suitable implantable cardioverter-defibrillators (ICDs). The Cardiovascular Committee of the EANM published Proposal for Standardization of 123I-metaiodobenzylguanidine (MIBG) Cardiac Sympathetic Imaging by the EANM Cardiovascular Committee and the European Council of Nuclear Cardiology in the European Journal of Nuclear Medicine and Molecular Imaging in 2010, and it is clear that the MIBG has a clinical application potential in cardiac sympathetic diagnosis.
Since its first clinical application report proposed by the University of Michigan in 1980, radioactive iodine labeled MIBG has been used clinically for 20 years. 131I and 123I-MIBG are radioisotopes of iodine. Although 123I-MIBG has the proper gamma ray (159 KeV), which makes it very suitable for imaging, its half-life period is only 13 hours. Therefore, the 123I-MIBG has to be produced by using middle-sized cyclotrons, which limits the transportation area thereof. I-131 labeled MIBG is mostly used for clinical diagnosis in foreign countries, and has been available on the market in Europe, America, Japan, and other countries. In 1994, The US Food and Drug Administration (FDA) also proved 131I-MIBG, which is called 131I intravenous agent (NDA 20-084), to be sold as a contrast medium for pheochromocytoma and neuroblastoma; in 2008, 123I-MIBG known as Iobenguane 123I-MIBG injection was also approved by the FDA (NDA 22-290) to be used as a tumor contrast medium (Adreview, GE Healthcare, Little Chalfont, UK), and in Europe, Japan, and other counties, it has been more than ten years since the 123I-MIBG and 131I-MIBG were allowed to go on sale.
The clinical application data of the MIBG is described as follows:
A. Imaging
In analysis and comparison of an MIBG imaging method and a fluorodeoxy-glucose-positron emission tomography (FDG-PET) method for neuroblastoma, imaging results of 21 neuroblastoma patients show that MIBG has higher sensitivity, especially at bones, while the FDG-PET has higher sensitivity at soft tissues. Therefore, the FDG-PET can compensate for the deficiency of MIBG. At present, computed tomography (CT) or magnetic resonance imaging (MRI) are the most commonly used for evaluating preliminary sites of tumors, and MIBG is applicable to imaging diagnosis after cancer metastasis.
During imaging using 123I, special attention should be paid to some factors that affects the imaging result, for example, drug interference, tumor periods, drug metabolism pathways, non-specificity of specific organs, and setting of imaging parameters. After false-positive and false-negative imaging results caused by specific factors are ruled out, 123I-MIBG is nearly 100% specifically bound to tumors, and is gathered in neuroblastoma cells after injection. Therefore, 123I-MIBG is a very useful tool for disease diagnosis, staging, and observation during treatment and prognosis.
B. Pharmacokinetics
After being injected intravenously, the MIBG is transmitted to neuroblast, and is mainly stored in cytoplasm of nerve cells. The MIBG is mainly excreted through the urinary system. One hour after the injection of the 131I-MIBG to neuroblastoma patients, 10% or lower of the 131I-MIBG still exists in the blood. 24 hours later, 57% of the 131I-MIBG is excreted out of the body through urine; and 48 hours later, 70% of the 131I-MIBG was excreted out of the body through urine. 90% of the MIBG is gathered in neuroblast, and the false-negative result is probably related to the change of the activity absorption mechanism caused by the differentiation of tumor cells or the drug interference.
The heart and salivary glands are controlled by sympathetic nerves, and the urinary tract and gastrointestinal system are MIBG excretion pathways. Therefore, these organs present very high MIBG expression. Intra-cavity non-specificity moves or decreases as the imaging time passes by, and can be easily distinguished during continuous image capturing.
C. Pharmacodynamics
The research report indicates that the treatment effective rate of 131I-MIBG on neuroblastoma is 30-40%. Most recent studies mainly focus on 131I-MIBG and chemotherapy and myeloablative stem cell transport combined therapies
D. Safety and Side Effects
The 131I-MIBG therapy has special side effects. The decrease degree of blood platelets and neutrophil leucocytes is associated with the therapy dosage absorbed by the body, because the specific absorption of megakaryocytes decreases bone marrow functions, especially when the 131I-MIBG therapy is performed after the chemotherapy. Despite the use of oral potassium iodide (KI), hypothyroidism still occurs. Other side effects include nausea and vomiting, chest pain, fever, and impact on liver and kidney; some studies show that oral mucositis and sialoadenitis may also occur.
When 123I-MIBG is used for diagnosis, 92-100% of the patients have accumulated 123I-MIBG in salivary glands, because the salivary glands are controlled by sympathetic nerves. 131I-MIBG has a high clearance rate; in this study case, the saliva-to-plasma ratio is greater than 1.0 (ranging from 15 minutes to 48 hours), and most radioactivity is excreted through saliva in the form of free 131I ions, which not only leads to an error in imaging diagnosis but also increases the radiological dosage on oral mucosa.
Therefore, the radioactive labeled MIBG has been popularized in imaging diagnosis. However, the radioactive labeled MIBG is radioactive, and therefore during manufacturing, operators are threatened by radiation contamination. Therefore, it is urgent to provide a device capable of automatically synthesizing, dispensing, and measuring radioactivity of radioactive labeled MIBG.